Written by Sandra Stranzinger
One of the biggest problems in the manufacturing of high-quality low-dose inhalation products, is dose uniformity of filled capsules [1]. Our approach towards a scientific qualification of dosator nozzles for low-fill weight (1–45 mg) capsule filling comprises a decoupling of the filling process in dynamic and static mode tests, whereas the latter was carried out using a novel filling system, i.e. stand-alone static test tool, developed by us.
Introduction
Precise dose filling in the lower mg-range, which is required for inhalation therapies [2], is essential for the successful manufacturing of high-quality products. Filling inhalation powders into capsules often requires specialized equipment that can handle the very low fill weight [3] in the range of a few tens of milligrams. For the currently available low-dose capsule filling systems, the dosator method is often used [4]. To date, although there is a considerable body of literature on identifying and assessing critical material and process parameters that affect the product quality for standard doses, little attention has been paid to low-dose dosator capsule filling processes. Recent studies of our working group [4, 5] demonstrated that the low-dose filling of very fine carriers with a dosator system is challenging, and further investigations are needed in order to achieve the required product specification compliance. Therefore, we developed a stand-alone static test tool with two primary aims:
- to investigate the effect of gaps between the dosator tip at the end of the stroke and the bottom of the powder container box (Figure 1) with different carrier materials. Although this process parameter is expected to affect the fill weight and weight variability, it has received too little attention to date.
- to take a closer look at the filling behavior of challenging fine carrier materials. It was assumed that the mechanical vibration of the powder drum induces particle movement/rearrangement in the drum and, possibly, segregation. To that end, the vibration present in the drum was measured to assess its intensity (specifically acceleration and frequency). Subsequently, the vibration was recreated in a laboratory setup to isolate the effect of vibrations, separating it from the dosing process and drum rotation.
Methods
Three grades of lactose excipients (Lactohale 100, Lactohale 200, Lactohale 220) that are commonly applied as carriers in inhalation therapies [2] were used as received from the supplier (DFE pharma, Goch, Germany). The various process steps of the capsule filling process were investigated by dynamic and static mode tests. Dynamic tests refer to filling of capsules in a regular lab-scale, low-dose dosator capsule filling machine (Labby, MG2, Bologna) with special low-dose equipment adaptions (i.e., smaller nozzles, a cleaning unit for the removal of excess powder from the dosator and special blades to create the powder layer). Static tests were conducted using a novel filling system developed by us. In both cases powders were filled into size 3 transparent hard gelatin capsules supplied by Capsugel with different dosing chamber lengths (2.5, 5 mm), dosator (nozzle) diameters (1.9, 3.4 mm) and powder bed heights (5, 10 mm), and, in the dynamic mode, with two filling speeds (500, 3000 capsules/h). The influence of the gap at the bottom of the powder container (Figure 1) on the fill weight and weight variability was assessed. Moreover, using an advanced experimental setup the effect of vibration on the filling performance of the highly cohesive Lactohale 220 was evaluated.
Figure 1: Sketch of the static test tool. The gap between the dosator tip and the bottom of the container are shown.
Results and Discussion
Results of different gaps indicated that, generally, the fill weight of all three powders in question was affected by varying the gaps, but in different ways. The most significant changes in the fill weight were observed for the highly cohesive powder, with a distinct correlation between the gaps and the fill weight: the smaller the gap, the higher the fill weight (Figure 3). Another significant finding of the static mode test was that with a low gap it was possible to fill the highly cohesive powder within a wide range, from 6 mg to 20 mg, with RSDs below 10% without any pre-compression. This is important with regard to filling capsules with very fine powders since compressing the powder into the dosator may lead to jamming the piston, blocking the dosator and terminating the process.
Figure 2: Adjustable instrumental settings; i.e. dosing chamber length, dosator (nozzle) diameter and powder layer (powder bed height), and, in the dynamic mode, filling speed (capsules/h).
Interestingly, in terms of vibration no change in the fill weight of the highly cohesive powder over time, as previously reported Stranzinger et al. [5], was observed in the static mode dosator dipping tests. This may be explained by the different modes of applied vibration (i.e., horizontal and vertical vibration), different sampling conditions and different powder layer re-conditioning strategies. One of the most striking observations to emerge from our study is that the sampling method, i.e., sampling with or without vibration, plays a key role in terms of weight variability. When using our new approach “dosing under vibration” a significant reduction of weight variability can be achieved. More precisely, for the highly cohesive powder the weight variability was reduced from 14.0% RSD to 4.5% RSD for adjusted vibration (i.e. vibration present at a capsule filling speed of 3000 capsules/h in dynamic mode) and from 18.8% RSD to 6.5% RSD under more intense vibration.
Figure 3: Fill weight and weight variability of Lactohale 220 for different gaps. Pbh = powder bed height, dcl = dosing chamber length, dia = diameter of dosator (nozzle).
Overall, our results indicate that by fine-tuning instrumental settings even very challenging powders can be filled with a low-dose dosator capsule filling machine. This study is a further step towards a scientific qualification of dosator nozzles for low-fill weight (1–45 mg) capsule filling.
Conclusion and Outlook
The findings suggest that for low-dose dosator capsule filling it is strongly recommended to continuously control instrumental settings, i.e., gaps between the lowest point of the dosator and the bottom of the box, as well as vibration that clearly affects the fill weight and weight variability. Researching the effect of certain process parameters of various powder materials on the filling performance provides valuable insights into a dosator nozzle filling process, step by step. Our results could help machine manufacturers to achieve product-specification compliance by fine-tuning the process parameters depending on the powders used.
Since this study was focused on the filling performance of pure carrier material, further research should be conducted to investigate the filling behaviour of powder mixtures (e.g., a powder with an API). In the end, a stepwise mechanistic process understanding could be developed, with the ultimate goal of creating a platform indicating the required instrumental settings for a range of various materials.
References
[1] N. Islam, M.J. Cleary, Developing an efficient and reliable dry powder inhaler for pulmonary drug delivery – A review for multidisciplinary researchers, Med. Eng. Phys. 34 (2012) 409–427. http://dx.doi.org/10.1016/j.medengphy.2011.12.025.
[2] X. Kou, L.W. Chan, H. Steckel, P.W.S. Heng, Physico-chemical aspects of lactose for inhalation, Adv. Drug Deliv. Rev. 64 (2012) 220–232.
[3] D. Edwards, Applications of capsule dosing techniques for use in dry powder inhalers, Ther. Deliv. 1 (2010) 195–201.
[4] E. Faulhammer, M. Fink, M. Llusa, S.M. Lawrence, S. Biserni, V. Calzolari, J.G. Khinast, Low-dose capsule filling of inhalation products: Critical material attributes and process parameters, Int. J. Pharm. 473 (2014) 617–626. http://dx.doi.org/10.1016/j.ijpharm.2014.07.050.
[5] S. Stranzinger, E. Faulhammer, V. Calzolari, S. Biserni, R. Dreu, R. Š, A. Paudel, J.G. Khinast, The effect of material attributes and process parameters on the powder bed uniformity during a low-dose dosator capsule filling process, 516 (2017) 9–20.
